1. Field of the Invention
Provided herein is a hydrogen chloride salt of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea, crystalline forms of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride, processes for the preparation of said crystalline forms, pharmaceutical compositions containing crystalline forms of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B, processes for the preparation of said compositions, pharmaceutical compositions prepared by said methods, and the use of said compositions in the treatment of various diseases and disorders.
2. Description of the State of the Art
The myelodysplastic syndromes (MDS, formerly known as pre-leukemia) are a diverse collection of hematological (blood-related) medical conditions that involve ineffective production (or dysplasia) of the myeloid class of blood cells. Patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and the patient develops cytopenias (low blood counts) due to progressive bone marrow failure. In about one third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years. The myelodysplastic syndromes include all disorders of the stem cell in the bone marrow. In MDS, hematopoiesis (blood production) is disorderly and ineffective. The number and quality of blood-forming cells decline irreversibly, further impairing blood production
The goals of therapy for patients with MDS are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML. Treatment options for patients with myelodysplastic syndromes range from supportive care that helps relieve symptoms to aggressive treatment that may slow or prevent progression of the disease. Problems caused by low blood cell counts, such as fatigue and infections, may be treated with transfusions of blood products or the use of growth factors. Chemotherapy may be used to delay progression of the disease. Other drug therapy may be used to lessen the need for transfusions. Certain patients may benefit from aggressive treatment with chemotherapy followed by stem cell transplant using stem cells from a donor. For patients with transfusion-dependent anemia due to low or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality, lenalidomide (Revlimid®) is an approved therapy in the United States. Other treatment options include immunosuppressive agents, low/intermediate intensity chemotherapy (e.g., azacitidine, decitabine, cytarabine), and finally high intensity antileukemic chemotherapy and hematopoietic cell transplantation. Accordingly, there remains a need for new pharmaceutical compositions and methods for treating MDS.
1-(3-Tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea (also known as “ARRY-614”) is exemplified in WO 2007/089646 and possesses the following structural formula:

1-(3-Tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea has been shown to possess potent inhibitory activity against the p38 MAPK and Tie2 protein kinases and therefore could be useful in the treatment of kinase-mediated conditions including proliferative disorders (such as myelodysplastic syndromes), inflammatory diseases, autoimmune diseases, destructive bone disorders, infectious diseases, viral disease, fibrotic disease and neurodegenerative diseases.
1-(3-Tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea has been tested in a Phase 1 human clinical trial for myelodysplastic syndromes (MDS) (see R. Komrokji, et al., “Phase 1 Dose-Escalation/Expansion Study of the p38/Tie2 Inhibitor ARRY-614 in Patients with IPSS Low/Int-1 Risk Myelodysplastic Syndromes”, 2011 Annual Meeting of the American Society of Hematology, Dec. 11, 2011; which can also be found at: http://www.arraybiopharma.com/_documents/Publication). In this study, a powder in capsule (“PIC”) composition of amorphous ARRY-614 was prepared and administered to patients with myelodysplastic syndrome, and inter-patient variability in exposure profiles (concentration/time profiles) and exposure PK parameters (AUC and Cmax) was high. In addition, the clinical study protocol required administration of 12×100 mg capsules per dose (i.e., once daily administration of 12×100 mg capsules), which arose from the inability to achieve a higher drug load per capsule of the amorphous form of the compound. This imposed an undesirably large pill burden on the patients. Due to the limitations of drug load per capsule, only a maximal administrable dose was reached but not a true maximum tolerated dose. A new formulation may provide greater dosing potential if needed.
In order to formulate a pharmaceutically active compound such as 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea into a suitably acceptable dosage form, it is desirable that the active compound possess acceptable stability and handling properties in addition to possessing acceptable biopharmaceutical properties such as solubility and dissolution. 1-(3-Tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea exists in an amorphous form. It is a BCS Class II molecule with low aqueous solubility (<10 μg/mL) across the typical physiological pH range of 2-8, with a ClogP 6.8 and a calculated pKa less than 3.
Bioavailability is one of the key parameters for many therapeutic indications and can be dependent on the form of the substance to be used in the pharmaceutical composition. Potential pharmaceutical solids of active drugs include crystalline solids and amorphous solids. It is known that the amorphous forms of many pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to the crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38:2003-2007). There is often a decrease in solubility of 12-1600 fold in going from an amorphous form to crystalline form (B. C. Hancock and M. Parks, Pharmaceutical Research, 2000, 17(4) 397-404). The identification and selection of a solid form of a pharmaceutical compound is complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, formulation, stability and bioavailability, among other important pharmaceutical characteristics. Drawbacks of using the amorphous form of a drug can include the potential of the amorphous solids to lack chemical and physical stability, as well as the risk of form conversion from amorphous to crystalline material at any time during manufacturing and/or storage. In addition, in some cases crystalline salts of the active drug do not form easily and/or are not stable, which is probably due to low pKa values. The pKa value expresses the strength of acids and base, i.e., the tendency for an acid to lose a proton or a base to add a proton (Bronsted J. N., Rec. Trav. Chim. (1923) 47:718).
There remains a need for a pharmaceutical composition suitable for treating proliferative diseases such as MDS.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea having increased exposure and increased relative bioavailability.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea having reduced inter-patient variability in pharmacokinetic profiles.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea having substantially similar pharmacokinetic profiles when administered to a mammal in the fed versus the fasted state.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea wherein smaller doses of the composition are required to obtain the same pharmacological effect.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea having acceptable pharmacokinetic properties at higher doses.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea having an increased rate of dissolution.
There also remains a need for a pharmaceutical composition containing a form of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea that is chemically and physically stable under the conditions in which it is processed, handled and stored.